This is a new R21 application to investigate potentially protective immune responses in individuals exposed to HIV-1 but who are HIV-1 uninfected. In our preliminary data, we have shown that anti-HIV-1 protease and anti-long-terminal interspersed nuclear elements (LINE) specific immune responses are detected in a large fraction of individuals exposed to HIV-1, but who are HIV-1 uninfected (exposed seronegatives, ESN). We hypothesize that exposure to HIV-1 and HIV-1 infected cell products have led to these responses, and that they may be partially responsible for prevention of establishment of an HIV-1 infection. The grant proposes in two specific aims to characterize the epitopes recognized by HIV-1 protease and LINE specific T cells in HIV-1 exposed uninfected subjects, and to determine the efficacy of anti-HIV-1 protease and LINE specific T cell clones to recognize HIV-1 infected cells in vitro and to suppress HIV-1 viral replication in a viral inhibition assay using primary isolates of a range of different viruses. The data generated from this grant would provide preliminary data for a future R01 to longitudinally follow a large cohort of ESNs to determine whether possession of such immunity was associated with protection from HIV-1 transmission. PUBLIC HEALTH RELEVANCE: This is a new R21 application to investigate potentially protective immune responses in individuals exposed to HIV-1, but who are HIV-1 uninfected.